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Toxicities Of Targeted
      Therapies
             R as h a H ag gag
             Md medical oncology
                          L/O/G/O
                    www.themegallery.com
Targeted Therapy in Oncology


Def: A drug with a focused mechanism that
specifically acts on a well-defined target or
biologic pathway that, when inactivated,
causes regression or destruction of the
malignant process.
Features of the Ideal Anticancer Target

 Crucial to the malignant phenotype.
 Not significantly expressed in vital organs and tissues.

 A biologically relevant molecular feature.

 Reproducibly measurable in readily obtained clinical
samples.
 Correlated with clinical outcome.

 Clinical response in a significant proportion of patients
whose tumors express the target when target interrupted,
interfered with, or inhibited.
Minimal responses in patients whose tumors do not express
the target.
Toxicities Of Targeted Therapies

•   Cardiovascular toxicity
•   Gastrointestinal toxicities
•   Renal toxicities
•   Skin toxicities
Cardiovascular toxicity of
 molecularly targeted agents


•Hypertension,
•Ventricular Dysfunction
• Qtc Prolongation
• Thrombo-embolic complications
Cardiac toxicity may be

• The on target effect : is caused by a
  target promoting both cancer cell growth
  and cardiomyocyte function.

• The off target effect : instead, occurs
  when a TKI causes an inhibition of a
  “bystander” target (i.e. a target not
  essential to kill cancer cells but involved in
  cardiomyocyte survival).
Cardiovascular toxicity of molecularly
 targeted agents



• Hypertension
• Ventricular Dysfunction
• Qtc Prolongation
1- Hypertension
Most common with drugs targeting
 angiogenesis through the vascular
 endothelial growth factor (VEGF) and/or its
 receptor (VEGFR) pathway:
• Monoclonal antibodies that bind the VEGF ligand (i.e.
    bevacizumab),
• Decoy VEGF receptors (i.e. aflibercept), and
• Small-molecule tyrosine kinase inhibitors of VEGFR
(i.e. sorafenib, sunitinib).
Vascular disrupting agents (VDAs) they disrupt the
    established abnormal vasculature that feeds tumors
    (exception ) not inhibit VEGF.
Mechanisms of hypertension of
            antiangiogenesis drugs:
1-VEGF is known to increase the synthesis of nitric oxide, a
   vasodilator, through upregulation of endothelial nitric
   oxide synthase. Anti-VEGF agents therefore decrease
   levels of endogenous nitric oxide n blood vessel walls,
   resulting in vasoconstriction and increased blood
   pressure.
2- VEGF inhibition also up-regulates baroreceptor
   function, increasing vascular tone.
3-Reduction in the number of arterioles and capillaries,
   which contributes to vascular stiffness and increased
   peripheral vascular resistance (rarefaction).
4 -Decreased sodium ion renal excretion and thus
   increased cardiac afterload.
Anti-VEGF agents reporting significant
hypertension in clinical trials
Evaluation of hypertension
1. Criteria for definition of hypertension:
 single gross elevation in blood pressure
  which is symptomatic (hypertensive
  urgency/emergency).
serial measurement of abnormal
  elevations of either systolic or diastolic
  blood pressure.
WHO/ISH definition and classification of blood
pressure levels




                                         110
NCI-CTCAE version 3.0 grades of HTN

Adverse event   Definition



Grade   1       Asymptomatic, transient increase; no treatment
                required

Grade   2       Recurrent, persistent or symptomatic increase;
                monotherapy may be required

Grade   3       Requiring more than one drug or more intensive
                therapy than previously

Grade   4       Life-threatening (e.g. hypertensive crisis)
2. Careful baseline assessment of cardiovascular risk is
     performed
3. patients with significant cardiovascular
disease within 6 to 12 months of anti-VEGF treatment
   initiation were generally excluded.
4- Comprehensive history and physical, as well as directed
   laboratory, investigations are also mandatory for
   cardiovascular risk stratification.
5- Individualised risk benefit analysis is recommended ,
   patients who are at very high risk pre-treatment
    would have been excluded from the anti-angiogenic
     clinical trials.
6- Current target blood pressure goals for cancer patients being
   considered for and receiving antiangiogenics:
• <140/90 mmHg
• <130/80 mmHg in diabetic and chronic renal dysfunction
    populations.
7- Once on therapy, it is imperative that regular and
comprehensive blood pressure monitoring occurs, with
initiation of anti-hypertensive agents if blood pressure
crosses accepted thresholds.
8- Clinical practice guidelines recommend blood pressure
monitoring weekly during the first cycle of therapy, and then at
   least every 2 to 3 weeks for the duration of anti-VEGF drug
   exposure
• Interestingly, there is a growing belief that
  hypertension may act as a valuable
  biomarker of efficacy with anti-VEGF
  agents.
• This was found with bevacizumab, axitinib
  and sorafenib and needs to proved in
  more prospective trials.
• Management of hypertension
A- non-pharmacologic interventions


• avoid excessive alcohol consumption and
  excessive salt intake ,
• Avoidance of other aggravating drugs
  such as non-steroidal anti-inflammatory
  drugs, steroids, erythropoietin agonists
  and sympathomimetics is also
  recommended when clinically feasible
B- Pharmacologic management

There is no consensus on recommendations
  of specific antihypertensive regimens used
  to manage HTN related to angiogenesis
  antagonists.
Treatment recommendations should be
  made on the basis of the potential risks
  and benefits associated with each unique
  drug and patient.
USE of ACE (angiotensin-converting enzyme)
  inhibitors may be beneficial as they affect nitric
  oxide.
The American Diabetes Association recommends
  use of angiotensin-receptor blockers as the
  treatment of choice in hypertensive patients with
  diabetes, frank proteinuria, and/or
  microalbuminuria.
Sunitinib: Diuretics remain the first-line choice for
  treatment of HTN in all patient populations,
  except those with chronic kidney disease (CRD).
Application of the general guidelines
C- Modification of the anti-VEGF agent
               dose or schedule.
• Depending on the type of anti-VEGF agent For
  patients receiving daily-dosed tyrosine kinase
  inhibitors of VEGF such as sunitinib or sorafenib,
  temporarily withholding or reducing the drug can be
  rapidly effective if hypertension is symptomatic or
  refractory to standard anti-hypertensive interventions.
• Anti-VEGF agents with longer half-lives such as
  bevacizumab and aflibercept do not respond as quickly
  to withdrawal or dose reduction. So:
• Do not start if ( systolic >160mmHg and diastolic
  >100mmHg), Aggressive anti-hypertensive efforts before
  ttt , close monitoring, if failed refer to hypertensive
  expert.
Cardiovascular toxicity of
         molecularly targeted agents




•   Hypertension,
•   Ventricular Dysfunction
•   Qtc Prolongation
•   Thrombo-embolic complications
Pathogenesis:

• Myocardial cells have limited regenerative capacity,
  which renders the heart susceptible to transient as well
  as permanent drug effects
• Drug-induced ventricular dysfunction can occur via
  several distinct mechanisms:
Type I cardiotoxicity, as caused by anthracyclines, results in
  structural abnormalities of the cardiac ultrastructure and subsequent
  cell death and clinical heart failure.
Type II cardiotoxicity ( induced by molecularly targeted agents
  (particularly trastuzumab) is caused by failure of myofibril contractile
  elements to exert coordinated activity, but cell death and clinical
  heart failure are not dominant features and is more likely to be
  reversible.
PATHOGENESIS of Trastuzumab
            cardiotoxicity

• Targeting ErbB2 (human epidermal growth
  factor type 2 / Her2) which has a role in
  normal myocyte function
• Induces mitochondrial apoptosis. Mitochondria are
    essential for myocyte vitality, as they generate
    adenosine triphosphate (ATP), the “fuel” for muscle
    contractility and survival.
It is possible that antibody dependent, cell-mediated
    cytotoxicity is a substantial contributor to impaired ErbB2
    function in myocytes, although this hypothesis remains
    theoretical and has not been scientifically substantiated.
Trastuzumab cardiotoxicity:
Incidence :
• In metastatic breast, trastuzumab administered in combination with
  anthracycline-based combination chemotherapy demonstrated a
  surprising 27% cardiotoxicity rate,versus 13% with chemotherapy
  alone.
• Adjuvant breast cancer trastuzumab trials indicates that grade
  3 or 4 cardiac toxicity occurred in 4.5% of patients receiving
  trastuzumab versus 1.8% in women who did not receive the drug.

Risk factors:
older age, concurrent administration chemotherapy or exposure to
   previous anthracyclines, baseline left ventricular dysfunction,
   coronary artery disease, uncontrolled hypertension, valvular heart
   disease, and cardiac arrhythmia. Non-cardiovascular risk factors
   may include chest wall radiation, diabetes and obesity .
Ventricular recovery is variable, ranging from 1.5 months to 1.5
   years, rechallenge after ventricular recovery is well
   documented
Cardiotoxicity associated with other
    molecularly targeted agents

• Lapatinib: low levels of cardiac toxicity of
• 1.5−2.2%, almost always reversible, and almost always
  asymptomatic.

• Sunitinib: mechanism uncertain, HF rate          2.7% to 11% with
   41% recovered. left-ventricular ejection monitoring, be incorporated
   into standard practice for patients receiving sunitinib.

• Imatinib: Severe congestive heart failure and left ventricular
   dysfunction have occasionally been reported in patients treated with
   imatinib. Patients with cardiac disease or risk factors for cardiac failure
   should be monitored carefully and any patient with signs or
symptoms consistent with cardiac failure should be evaluated and treated

• Bevacizumab and Alemtuzumab
An oncologist’s approach to ventricular
                       dysfunction
1.   Baseline assessment of their LVEF.
2.   Only patients with normal cardiac function and
     no symptoms of congestive heart failure as
     quantified by the New York Heart Association
     (NYHA) classification system should be treated
     with a potentially ventricular-toxic agent.
3.   Regular monitoring with physical examination
     as well as radiological measurement of left
     ventricular ejection fraction should ensue.
4.   Any symptoms or signs suggestive of heart
     failure, functional cardiac assessment should
     occur.
MANAGEMENT

Once significant cardiac dysfunction is demonstrated,
  molecularly targeted therapy should be interrupted and
  aggressive management of heart failure should be
  implemented.
• No specific strategy, so general population guidelines
  should be followed.
• Serial reassessment of cardiac status is needed once
  dysfunction is demonstrated, rechallenge was tolerable
  with trastuzumab but follow-up is immature.
Cardiovascular toxicity of
         molecularly targeted agents




•   Hypertension,
•   Ventricular Dysfunction
•   Qtc Prolongation
•   Thrombo-embolic complications
Background and mechanisms of QT
prolongation


                   • On the ECG, the QT
                     interval is measured
                     from the beginning of
                     the QRS complex to
                     the end of the T wave
                     in the lead without
                     prominent U waves.
• The QT interval on the ECG is a measure of ventricular
  depolarisation and repolarisation, corresponding to the
  duration of the ventricular action potential.

• The interval is known to have biologic variation, most
  importantly with gender and heart rate. Formulae exist to
  account for these biologic confounders, and “corrected”
  QT (QTc) measurements of 450ms for men and 470ms
  for women are generally accepted as the upper limit of
  normal.

• Ventricular arrhythmias, particularly torsade de pointes
  (TdP), correlate with a QTc interval of more than 500ms
Causes of prolonged QT interval
Nilotinib




arsenic trioxide               Prolongation of the QTc Interval
•     The FDA has provided specific safety guidelines
    for QTc interval monitoring with arsenic trioxide
    administration (applicable when using other drugs):

All patients must demonstrate a baseline QTc (best
    determined as a mean of three electrocardiograms
    more than 5 minutes apart) less than 500 ms, as well
    as maintain serum potassium greater than 4 mEq/L
    and magnesium greater than 1.8 mg/dL.
If the QTc interval is greater than 500 ms or symptoms
    of syncope or palpitation occur, electrolyte
    replenishment and immediate hospitalization are
    advised, with cessation of arsenic trioxide treatment
    until QTc less than 460 ms.
Cardiovascular toxicity of
        molecularly targeted agents




•   Hypertension,
•   Ventricular Dysfunction
•   Qtc Prolongation
•   Thrombo-embolic complications
• Bevacizumab :
A. Arterial thromboembolic events (ATEs):
• Included cerebral infarction, transient ischemic attacks
  (TIAs), myocardial infarction (MI), and angina.
• More frequently (4.4 versus 1.9%) and were more often
  fatal (0.7 versus 0.4%) in patients receiving
  bevacizumab in combination with chemotherapy
  compared with those receiving chemotherapy alone.
• There is an increased risk of any ATE in bevacizumab-
  treated patients who have a prior history of stroke/heart
  attack (~5 fold), in those aged 65 years (~3 fold) and in
  patients with hypertension (~2 fold). Bevacizumab
  should be permanently discontinued in patients who
  develop ATEs.
• Bevacizumab :
B . Venous thromboembolic events (VTEs):
• Include deep venous thrombosis, pulmonary embolism
  and thrombophlebitis.
• VTEs occurred more often in patients receiving
  bevacizumab with chemotherapy than in those receiving
  chemotherapy alone.
• If any grade 3-4 VTE occurs in a clinical trial, dosing
  with bevacizumab should be stopped for 3 weeks.
  Administration should only be continued when
  anticoagulation parameters have stabilised. Patients with
  symptomatic pulmonary embolism must not be treated
  with bevacizumab
• IMMUNOMODULATORY AGENTS

 Thalidomide and Lenalidomide use is
 associated with significantly increased
 incidence of deep venous thrombosis.
Prophylactic anticoagulation is
 recommended during therapy of either
 drug.
Skin toxicities of
targeted therapies

                         L/O/G/O
                www.themegallery.com
• Skin Toxicity Of Epidermal growth
  factor receptor (EGFR) inhibitors.

• Skin Toxicity Of Multikinase inhibitors
  (sorafenib, sunitinib,imatinib)
• Skin Toxicity Of Epidermal growth
  factor receptor (EGFR) inhibitors.

• Skin Toxicity Of Multikinase inhibitors
  (sorafenib, sunitinib,imatinib)
Epidermal growth factor receptor (EGFR)
                      inhibitors
• EGFR targeted drugs consist of monoclonal antibodies
  to EGFR (e.g. cetuximab, panitumumab),
• small-molecule tyrosine kinase inhibitors specific for
  EGFR (e.g. erlotinib, gefitinib),
• dual kinase inhibitors inhibiting EGFR and HER2
  (lapatinib),
• pan-erbB inhibitors inhibiting EGFR and other erbB
  receptors (canertinib)
• and other less specific inhibitors such as vandetanib
  inhibiting EGFR, vascular endothelial growth factor
  receptor (VEGFR) and RET.
Clinical picture
• Probably owing to the abundant expression of
  EGFR in the epidermis and its appendages (hair
  follic.
• EGFR-inhibitor-induced skin toxicity consists
  of : an acneiform eruption, skin dryness
  leading to eczema and fissures, nail changes,
   hair changes, telangiectasia,
  hyperpigmentation and mucosal changesles,
  sebaceous glands)
Acneiform eruption
• The most frequently reported side effect of EGFR
  inhibitors is a dose-dependent acneiform eruption,
  occurring in 50% to 100% of patients.
• The eruption is more or less confined to the
  seborrheic areas (rich in sebaceous glands): the
  face (especially the nose, the cheeks, the forehead
  and the chin), the scalp, the neck and retroauricular
  area,the shoulders and the upper trunk (typically V-
  shaped).
The eruption tends to be more severe and
  widespread with monoclonal antibodies than with
  oral tyrosine kinase inhibitors (for which gastro-
  intestinal toxicity is a dose-limiting factor)
• The skin lesions consist of sometimes itchy,
  erythematous follicular papules that may evolve into
  pustules.

• The papulopustular eruption can appear just a few days
  (2−3 days for biologics, 7−10 days for small molecules)
  after treatment with the EGFR inhibitor, often reaching a
  maximum 2 to 3 weeks following initiation of therapy.

• Slow spontaneous improvement of the rash is the rule
  when the EGFR inhibitor is continued even in the
  absence of dermatologic supportive treatment .
• Flare up of the rash can occur following each
  infusion (in the case of intravenously
  administered monoclonal antibodies) and Sun
  exposure .
• Acneiform eruption by EGFR inhibitors is
  essentially sterile but superinfection with
  Staphylococcus aureus may occur.
• Skin areas that previously underwent
  radiotherapy are characteristically spared from
  the acneiform eruption. Concomitant cetuximab
  and radiotherapy on the other hand appear to
  increase the incidence of severe radiodermitis.
EGFR-inhibitor-induced rash is acneiform should
  clearly be distinguished from acne vulgaris: indeed,
  comedones (blackheads and whiteheads) − the hallmark
  of true acne are lacking and so are nodules.

Moreover, itchiness is not infrequent in EGFR inhibitor-
 induced acneiform but is absent in acne vulgaris. Finally,
 scalp involvement is rare in acne but frequent in
 patients receiving EGFR inhibitors.
Xerosis, eczema and fissures
• EGFR inhibitors often gradually develop a dry
  skin over weeks.
• Old patient age, previous therapy with cytotoxics
  and a history of atopic eczema will accentuate
  the cutaneous dryness, which manifests with
  dry, scaly, itchy skin.
• The xerosis may develop into chronic asteatotic
  eczema
• secondary infection
• Painful fissures
Nail changes
• In 10−15% of patients, do
  not start earlier than 4−8
  weeks after the initiation
  of the EGFR inhibitor
• Paronychia very painful
  inflammation of the nail
  fold. (caused by
  epidermal cell growth
  arrest and differentiation
• Induced by the EGFR
  inhibitor)
Hair changes
• Very characteristic
are the long, curly, rigid
  eyelashes, termed
Trichomegaly
• The eyebrows
  become thicker and
  more rigid as well,
  with lateral thinning.
• Slow growth of scalp
  hair,and beard.
Other skin toxicities
• Telangiectasia
• The telangiectasia together with facial
erythema, tenderness and follicular papulopustules
in the absence of comedones creates a rosacea-like
picture of the face. Unlike other telangiectasia, the
lesions tend to fade over months usually leaving some
hyperpigmentation
• Hyperpigmentation
• Mucosal changes:
Conjunctivitis,.
Dry mouth, apthous stomatitis.
dry vulvovaginitis (especially in postmenopauzal (women) or
   balanitis.
Treatment of
EGFR-inhibitor
 skin toxicity
General measures and treatment
     principles
• Adequate sun protective measures
• avoid skin care products that dry out the skin
• An emollient/hand cream can be used on the limbs and
   hands to prevent xerosis and fissures
• Prophylactic treatment of acneiform eruption, as it occurs
in 80% of patients on EGFR inhibitors:
Minocycline 100 mg qd , oral tetracycline 500 mg bid and a
   regimen consisting of doxycycline 100 mg bid,
topical hydrocortisone 1%, emollients and a sunscreen
decreased severity of acneiform eruption.
Treatment of acneiform eruption

• Topical metronidazole and oral
minocycline are the standard of treatment.
• As a topical therapy, metronidazole is preferred
  (as a 2% preparation in cetomacrogol cream or
  as 0.75% Rozex® cream) because of its
  mildness, as it is normally used for the very
  sensitive skin of rosacea patients, twice a day or
  in between as needed on the first appearance of
  papulopustular lesions
• Topical retinoids (adapalene, tazarotene) are
  used by some but lack rationale.
• Acneiform eruption-associated itchiness can
  easily be controlled with an oral antihistaminic.
• Calcineurin antagonists (tacrolimus or
pimecrolimus), being used as first-line therapy in
  some American centres(irritant ,expensive)
• Topical menadione (vitamin K3, an EGFR
  phosphatase inhibitor with promising
• preclinical properties), not yet available for
  clinical use
•     Despite its efficacy for EGFR inhibitor-dependent
rash, oral isotretinoin should not be used as it may
  possibly interfere with EGFR-inhibitor antitumor activity
  by down regulating EGFR expression.
Moreover, isotretinoin shares a large number of side effects
  with EGFR inhibitors (xerosis, sensitivity for S. aureus
  superinfection, paronychia, pyogenic granuloma), which
  may lower tolerability.
• Systemic steroids are also to be avoided in the
  treatment of acneiform eruption as they may induce a
  similar eruption themselves; in addition, they may
  hamper the antibody-dependent cell-mediated
  cytotoxicity that is ascribed to EGFR-antibodies
Treatment of xerosis, eczema and fissures
• Hydrating measures oil in water creams (e.g.
  metronidazole cream) On the limbs, greasy (water in oil)
  creams or even ointments can be used for moderate to
  severe xerosis.
• Eczema :a topical weak to medium strength corticosteroid
  cream is recommended for a short term (1 to 2 weeks).
• Salicylic acid : fingertip eczema.
• Infection :Treatment with topical (e.g. fusidic acid) or, in
  severe cases, systemic anti-S. aureus antibiotics can be
  added for 5−10 days.
• Fissures: propyleneglycol 50% aqueous solution under
  plastic occlusion/salicylic acid 10% ointment, a
  hydrocolloid dressing or liquid cyanoacrylate glue
Treatment of paronychia

Antiseptic (e.g. chloramine, polyvidon iodine)
  oaks or creams are advised on a daily basis.
  When superinfection is suspected, swabs can
  be taken and oral anti-S. aureus antibiotics (e.g.
  flucloxacillin) given anti-yeast (e.g. nystatin) and
a potent topical corticosteroid. Oral nonsteroidal
anti-inflammatory drugs can be administered
to control the pain. Silver nitrate application on a
weekly basis improves pyogenic granuloma
Treatment of hair changes, hyperpigmentation and
                      telangiectasia

• Eyelashes         : laser epilation.
• Telangiectasia : electrocoagulation or pulsed dye laser
  therapy.
• Treatment of mucosal changes:
• Eye : attificial tears, topical steroids,antibiotic
• Tetracycline or antiseptic mouthwash alleviates
• stomatitis symptoms. For aphtous ulcers of the
  mouth,topical steroids or anaesthetics can be used.
• Dryness of the nose or the vagina responds fairly well
  to lubricants or ointments containing an antibiotic or
  antiseptic.
Associations with outcome of therapy,
                predictive role
Most of the published data have shown that patients in
  whom skin toxicity develops show a higher response
  rate than those without rash and significant
  correlations between occurrence of rash and
  increased survival have been found, with a trend
  towards improved overall survival and longer
  progression-free survival with increasing severity of
  rash.

• Some research groups state that the rash is a surrogate
  indicator of an adequate degree of receptor saturation by
  EGFRI.
• Skin Toxicity Of Epidermal growth factor
  receptor (EGFR) inhibitors.

• Skin Toxicity Of Multikinase inhibitors
  (sorafenib, sunitinib,imatinib)
Clinical picture
Sorafenib (34%) and sunitinib (19%) may
  cause
1-hand-foot skin reactions (HFSR)
•   Dose-dependent.
•   Very characteristically localised to skin areas of friction
  or pressure.
• It emerges in the first 2−3 weeks of treatment as sharply
  demarcated, erythematous, painful, oedematous and
  blistering lesions that evolve into extremely tender,
  inflamed calluses
2- Asymptomatic subungual splinter haemorrhages
are seen in not less than 40−70% of patients on sorafenib or sunitinib.
    Sensitivity of subungual capillaries to microtrauma due to inhibition of
    VEGFR (with impaired angiogenesis) may be involved in its
    pathogenesis.
3- Dryness of the skin and/or mucous membranes
   (occasionally with stomatitis) are present in approximately
     25% of patients receiving sorafenib/sunitinib.

4 . In the first weeks of treatment, sorafenib (and
    more rarely sunitinib) may cause a sometimes flaky erythema of the
    scalp and the face sparing the periorbital area, temporary alopecia, a
    transient dysaesthesia of the scalp skin with a burning and painful
    sensation, transient maculopapular rash.
5- Sunitinib: a yellow skin discolouring, caused by accumulation of this
    yellow molecule in the integument, reversible hair depigmentation,
    facialoedema.
• Various skin reactions have been
  described with Imatinib:
• A dose-dependent, periorbital, facial or even generalised
  oedema, appearing 2 weeks after starting the drug with very
  gradual regression later on.
• Maculopapular eruptions (and, rarely, even more
   severe drug reactions such as vasculitis, acute generalised
  exanthematous pustulosis or toxic epidermal necrolysis
  necessitating permanent drug withdrawal).
• Skin depigmentation but seldom also a paradoxical
  hyperpigmentation (especially of the nails) or repigmentation
   of grey hair.
• Xerosis cutis and pruritus.
Treatment and clinical management
• To minimise the impact of hand-foot skin reaction: avoid drying
  of the skin; avoid friction and wear comfortable fitting clothes and
  shoes; treat pre-existing calluses or hyperkeratoses or mild hand-
  foot skin reaction with urea- or salicylic acid ointment.
• Moderate HFSR: ultrapotent topical steroids and topical lidocaine
  to control the pain. Oral analgetics can be added accordingly.
• For severe reactions, a (temporary) dose adjustment or
  interruption of the multikinase inhibitor is proposed when supportive
  dermalogic treatment offers insufficient relief.
• Xerosis cutis: emollients and sometimes oral antihistamines.
• The seborrheic dermatitis-like facial lesions respond well to topical
• ketoconazole or weak steroids.
• For the maculopapular eruption with sorafenib or imatinib, topical or
  systemic steroids and sometimes interruption of the drug are
  advised
Renal toxicities of
molecular targeted
    therapies:


                           L/O/G/O
                  www.themegallery.com
Classification
A. Nephron structure damage
Glomerular lesions
Glomerulonephritis and proteinuria

Tubular lesions
Fanconi syndrome or renal tubular acidosis
Distal tubular alteration

Interstitial lesions
Allergic interstitial nephritis

B. Vascular lesions
 Renal thrombotic microangiopathy
Glomerulonephritis and proteinuria

• Most of the toxicity is related to anti-VEGF

• In the kidney, VEGF maintains the glomerular
  and peritubular capillary network. Use of an anti-
  VEGF agent may therefore disturb this network
  of blood vessels, leading to glomerular
  dysfunction and proteinuria.(altered glomerular
  permeability).
• VEGF can act as a survival factor for podocytes
  and thereby prevent glomerulonephritis
Glomerulonephritis

• Different types of glomerulonephritis have
  been described during the use of
  molecular targeted therapies including:
• membranoproliferative
  glomerulonephritis ,
• minimal change disease,
• cryoglobulinemic glomerulonephritis
 and focal segmental glomerulosclerosis.
Proteinuria:
Proteinuria:
Bevacizumab               21- 41%     low dose G3
                          22- 63%     high dose

VEGF TKIs                 Proteinuria and HTN
                          Oedema as a direct consequence of
                          proteinuria (it is one of the
                          dose-limiting toxicities of sunitinib)

MTOR    inhibitors        •increase in glomerular capillary
                          pressure or directly by increasing
Temsirolimus, sirolimus   glomerular permeability/ injury.
                          •Podocyte injury and focal segmental
                          glomerulosclerosis
Proteinuria should be monitored in patients
  receiving anti-VEGF therapy using the urine
  protein to creatinine ratio.
• This index of proteinuria is commonly used in
  the nephrology literature and correlates well with
  24-h protein excretion.
• Dipstick values 2 or higher should be confirmed
  by the ratio of urine protein to creatinine or 24-h
  collection.
• Bevacizumab therapy It is known that under this
  medication treatment should be interrupted in
  patients with proteinuria greater than 2 g/24 h
Tubular lesions
1. Fanconi syndrome or renal tubular acidosis
• imatinib : failure to reabsorp bicarbonate , and to
  secrete acid . Dysfunction of the proximal tubular cells
  and with phosphaturia, glycosuria, aminoaciduria,
  uricosuria and tubular proteinuria The principal feature of
  Fanconi’s syndrome is bone demineralisation due to
  phosphate wasting. This syndrome has been reported
  with different TKIs like imatinib
2. Distal tubular alteration
 This alteration is characterised by hypomagnesaemia.
This phenomenon is one of the most frequent toxicities
  described with antibodies against EGFR.
• Low Mg2+ inhibits endothelial migration and
  proliferation, late events absolutely required for the
  formation of new vessels, by desensitising endothelial
  cells to the effects of angiogenic factors.
• The interaction between anti-EGFR agents and
   Mg2+ homeostasis could be partially responsible for
   the anticancer activity of these agents.
• During anti-EGFR antibodies therapy, in addition to
  baseline assesment, serum Mg2+ level should be
  measured when fatigue or hypocalcaemia is
  encountered, and repleted as necessary
Interstitial lesions
• Common types of tubulointerstitial injury that can
  occur secondary to therapeutic agents include
  allergic interstitial nephritis, acute tubular
  necrosis, crystal nephropathy, tubular atrophy,
  and interstitial fibrosis
• Allergic interstitial nephritis:
Bevacizumab,sunitinib , progressive kidney
  dysfunction with proteinuria, together with
  peripheral eosinophilia and eosinophiluria, fever
  and rash
Ttt : corticosteroids
Vascular lesions
• Renal thrombotic microangiopathy
  sirolimus, bevacizumab, sunitinib
• Usually, withdrawal of the causing drug results in
  complete recovery or at least significant
  improvement of hypertension and renal
  involvement.
• But, as limited therapeutic options, the
  alternative of maintaining treatment while
  blocking the renin–angiotensin system could be
  a good strategy for hypertension and proteinuria
  control
• Combinations and interactions with
  other neprohotoxic drugs
• Most of the experience of targeted
  therapies in combination with
  chemotherapy has been gained with
  bevacizumab and cetuximab no increase
  in toxicity was found .
Gastrointestinal toxicities of
  novel agents in cancer
          therapy


                               L/O/G/O
                      www.themegallery.com
Include:

• Diarrhoea
• Gastrointestinal bleeding,
  gastrointestinal perforation and wound-
  healing problems.
• Hepatic toxicity.
• Elevation of pancreatic enzymes
Incidence, clinical pattern and
   pathophysiology of diarrhoea
1. Anti-epidermal growth factor receptor (EGFR) therapies
• Appears withen 2 weeks after treatment initiation .
• Correlated with the dose not plasma conc.
• Mechanism :
1. EGFR are widely expressed in the normal colic mucosa in
    which they regulate both chloride secretion and sodium
    absorption by colonocytes . Therefore, EGFR
     inhibition can subsequently lead to secretory diarrhoea.
2. is also described to be involved in the maintenance of mucosal
    integrity. the stimulation of mucin production and the enhancement
     of prostaglandin synthesis.
4. Inhibition of EGFR might therefore lead to digestive lesions.
Diarrhoea occurs in about 20−28% of patients
undergoing anti-EGFR monoclonal antibody
  therapy but is rarely severe: 1−2% of grade 3−4.
The incidence and severity of diarrhoea is higher
  with EGFR-TKIs than with anti-EGFR
  monoclonal antibodies, which have an incidence
  of 50−60% including 5% grade 3−4; diarrhoea is
  a dose limiting toxicity for TKIs.
• Diarrhoea related to drug toxicity was also
  correlated in some studies with a clinical benefit
  and/or was a predictive factor of tumour
  response to TKI
2. Anti-HER2 (ErbB2) therapies
• Trastuzumab is rarely associated with diarrhoea, with a
  total incidence of 7% without any grade 3−4 toxicity.
• Lapatinib : diarrhoea occurred in 55% of lapatinib-
  treated patients versus 24% of controls, grade 3
  occurred in 9%.
• 40% of patients had the first episode of diarrhoea within
  6 days after drug introduction for a median duration was
  of 7−9 days.
• Diarrhoea was dose related and not associated with
  serum concentration.
3. Multi-targeted kinase inhibitors
• Imatinib: 40% of patients, less than 5%, grade
  3−4 diarrhoea.
• The mechanism remains unknown, but one
  hypothesis is the inhibition of the colonic pace-
  maker cell (Cajal cells) which are c-Kit positive.
• Sunitinib :D 20% of treated patients including
  3% with grade 3 but no grade 4 diarrhoea.
• Sorafenib: 39% of patients, 8% grade 3 and no grade
  4. Diarrhoea was the most frequent adverse event that
  led to dose reduction (8% of cases)
• Nilotinib: D in less than 10% of patients with only 1%
  grade 3−4.
• Dasatinib : all grades of diarrhoea
• in about 50% of patients, including 6% of grade 3−4.
4. Anti-angiogenic therapies:
• Bevacizumab: diarrhoea occurred in only 12% of
  patients with no grade 3 or 4 diarrhoea.
5.Others
• Temsirolimus: 27% of patients with less than 1% grade
  3−4.
• Bortezomib: all grades 30−40% grade 3 4−8% , no grade 4
  diarrhoea. watery, with no bleeding, and associated with mild to
  moderate abdominal pain and cramps. Symptoms occur within the
  first 12−18 h after infusion initiation, and lasts for 1−2 days
Management of diarrhoea in patients
     undergoing targeted therapy
1.   It is important to exclude another cause of diarrhoea to avoid
     inappropriate treatment discontinuation. Exclude concomitant
     intake of laxative treatment, a past history of gastrointestinal tract
     surgery or look forClostridium or another infection.

• 2. In most patients, diarrhoea resolves with conventional
   approaches, without dose modification It can be useful to rapidly
  start loperamide treatment with the classic administration of two 2
  mg tablets after the first occurrence of diarrhoea followed by one
   tablet after consecutive episodes every 4 h.

3. In a minority of patients (<5% of cases), but particularly with orally
    administered small molecules, dose modification or treatment
    discontinuation is necessary .
4. If diarrhoea does not respond to limited
  intervariations, a dose of 0.5 mg subcutaneously
  (s.c.) of octreotide acetate every 8 h for 48−96 h
  may be recommended when diarrhoea is
  resistant to loperamide. Octreotide should be
  discontinued within 24 hours after the resolution
  of diarrhoea.
5- Severe diarrhea : hospitalisation for evaluation,
  intravenous fluid administration and electrolyte
  correction and/or antibiotics
• Wound-healing complications,
   Gastrointestinal bleeding and
  gastrointestinal perforation
• Wound-healing complications
• Angiogenesis is one critical mechanism in the complex process of
  wound healing and bevacizumab, as an anti-angiogenic agent, has
  the potential to disrupt wound healing.
• Bevacizumab is also associated with wound-healing
  complications in about 2−4.5% of patients who had
    surgery after treatment initiation.
• Since the half-life of bevacizumab is approximately
   21 days, it is recommended that therapy should not be
   initiated for at least 28 days following major surgery or
   until the wound is fully healed.
• Furthermore, bevacizumab should be withheld 28−42
   days before elective surgery.
Gastrointestinal perforations

• GI perforation (i.e., GI perforation, fistula formation,
  and/or intra-abdominal abscess), occurred in 2.4% of
  patients receiving bevacizumab alone or in combination
  with chemotherapy in 3 clinical trials for metastatic
  colorectal cancer.
• life-threatening condition,fatal in 30% of cases.
• Manifestations of these adverse GI effects included
  abdominal pain with constipation and vomiting (emesis).
• The mechanism unknown. may be due to the
  shrinkage of tumour masses embedded in the intestinal
  wall, or may occur at the site of previous surgery. Other
  risk, factors include abscesses, diverticula or an
  inflammatory process involving the GI tract
Gastrointestinal bleeding
• Bevacizumab: Severe or fatal hemorrhages,
  including hemoptysis, GI bleeding, hematemesis, CNS
  hemorrhage, epistaxis, and vaginal bleeding, occurred
  up to fivefold more frequently in patients receiving
  bevacizumab and chemotherapy than in those receiving
  chemotherapy alone.
• sorafenib : was not associated with digestive
  haemorrhage or variceal bleeding in cirrhotic patients
  treated for hepatocellular carcinoma.
• Imatinib, at a high dose of 800 mg/d was
  responsible for digestive haemorrhage-related
  death in four patients
Targeted therapy and hepatic
  toxicity
• Kit and PDGFR inhibitors
 Imatinib
 Sunitinib
• Anti- EGRF :
 Gefitinib
 Erlotinib
 Anti HER2:
 Lapatinib (rare reversible)
 Anti VEGF :
 Bevacizumab (sclerosing cholangitis)
Imatinib hepatic toxicity
• In clinical trials, severe hepatotoxicity occurs in less than
   5% of patients.
• To date, a total of 24 case reports of severe
   hepatitisinduced by imatinib have been published.
• Little is known about the mechanisms of liver
toxicity but imatinib is metabolised by cytochrome
P450. Therefore, an increase in toxic metabolites is
possible in cases where there is use of enzymatic
Inducers.
• Also An idiosyncratic mechanism and an immuno-
   allergic mechanism were probable.
Liver tests and prothrombin time should be
  performed before initiation of imatinib and then
  weekly or twice a month in the first month and
  then monthly thereafter or in case of symptoms.

• Treatment has to be withdrawn in cases of
  grade-3 hepatotoxicity. Some authors have re-
  introduced imatinib at slowly increasing doses
  together with prednisone without recurrence of
  liver injury,, others suggest to modify the
  schema of treatment administration
In conclusion, little is known about the mechanisms
of hepatotoxicity due to targeted agents and management
is often empirical.
One should be cautious with the use of enzymatic inducers or inhibitors
    together with agents metabolised by the cytochrome pathway
(e.g. imatinib, gefitinib, erlotinib).

Hepatic function tests should be performed regularly . In case of liver
  dysfunction, other aetiologies should be ruled out and the use of
  the adverse drug reaction probability scale will help to evaluate the
  relationship between drug and hepatotoxicity.
Elevation of pancreatic
           enzymes



Elevation of lipase can be observed with the
  small oral multi-targeted therapies
  sorafenib, sunitinib and nilotinib.
Recommendations of tests according to
            treatment
Side effects and organ toxicity of protein
   kinase inhibitors observed in clinical
                  studies.
Take home message

• Although novel, molecular targeted
  therapies are starting to fulfil their promise,
  changing how patients with cancer are
  treated and altering the natural history of
  many types of cancer, they are far from
  being a “magic bullet.”
Toxicities of targeted therapies

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Toxicities of targeted therapies

  • 1. Toxicities Of Targeted Therapies R as h a H ag gag Md medical oncology L/O/G/O www.themegallery.com
  • 2. Targeted Therapy in Oncology Def: A drug with a focused mechanism that specifically acts on a well-defined target or biologic pathway that, when inactivated, causes regression or destruction of the malignant process.
  • 3. Features of the Ideal Anticancer Target  Crucial to the malignant phenotype.  Not significantly expressed in vital organs and tissues.  A biologically relevant molecular feature.  Reproducibly measurable in readily obtained clinical samples.  Correlated with clinical outcome.  Clinical response in a significant proportion of patients whose tumors express the target when target interrupted, interfered with, or inhibited. Minimal responses in patients whose tumors do not express the target.
  • 4. Toxicities Of Targeted Therapies • Cardiovascular toxicity • Gastrointestinal toxicities • Renal toxicities • Skin toxicities
  • 5. Cardiovascular toxicity of molecularly targeted agents •Hypertension, •Ventricular Dysfunction • Qtc Prolongation • Thrombo-embolic complications
  • 6. Cardiac toxicity may be • The on target effect : is caused by a target promoting both cancer cell growth and cardiomyocyte function. • The off target effect : instead, occurs when a TKI causes an inhibition of a “bystander” target (i.e. a target not essential to kill cancer cells but involved in cardiomyocyte survival).
  • 7. Cardiovascular toxicity of molecularly targeted agents • Hypertension • Ventricular Dysfunction • Qtc Prolongation
  • 8. 1- Hypertension Most common with drugs targeting angiogenesis through the vascular endothelial growth factor (VEGF) and/or its receptor (VEGFR) pathway: • Monoclonal antibodies that bind the VEGF ligand (i.e. bevacizumab), • Decoy VEGF receptors (i.e. aflibercept), and • Small-molecule tyrosine kinase inhibitors of VEGFR (i.e. sorafenib, sunitinib). Vascular disrupting agents (VDAs) they disrupt the established abnormal vasculature that feeds tumors (exception ) not inhibit VEGF.
  • 9. Mechanisms of hypertension of antiangiogenesis drugs: 1-VEGF is known to increase the synthesis of nitric oxide, a vasodilator, through upregulation of endothelial nitric oxide synthase. Anti-VEGF agents therefore decrease levels of endogenous nitric oxide n blood vessel walls, resulting in vasoconstriction and increased blood pressure. 2- VEGF inhibition also up-regulates baroreceptor function, increasing vascular tone. 3-Reduction in the number of arterioles and capillaries, which contributes to vascular stiffness and increased peripheral vascular resistance (rarefaction). 4 -Decreased sodium ion renal excretion and thus increased cardiac afterload.
  • 10. Anti-VEGF agents reporting significant hypertension in clinical trials
  • 11.
  • 12. Evaluation of hypertension 1. Criteria for definition of hypertension:  single gross elevation in blood pressure which is symptomatic (hypertensive urgency/emergency). serial measurement of abnormal elevations of either systolic or diastolic blood pressure.
  • 13. WHO/ISH definition and classification of blood pressure levels 110
  • 14. NCI-CTCAE version 3.0 grades of HTN Adverse event Definition Grade 1 Asymptomatic, transient increase; no treatment required Grade 2 Recurrent, persistent or symptomatic increase; monotherapy may be required Grade 3 Requiring more than one drug or more intensive therapy than previously Grade 4 Life-threatening (e.g. hypertensive crisis)
  • 15. 2. Careful baseline assessment of cardiovascular risk is performed 3. patients with significant cardiovascular disease within 6 to 12 months of anti-VEGF treatment initiation were generally excluded. 4- Comprehensive history and physical, as well as directed laboratory, investigations are also mandatory for cardiovascular risk stratification. 5- Individualised risk benefit analysis is recommended , patients who are at very high risk pre-treatment would have been excluded from the anti-angiogenic clinical trials.
  • 16.
  • 17. 6- Current target blood pressure goals for cancer patients being considered for and receiving antiangiogenics: • <140/90 mmHg • <130/80 mmHg in diabetic and chronic renal dysfunction populations. 7- Once on therapy, it is imperative that regular and comprehensive blood pressure monitoring occurs, with initiation of anti-hypertensive agents if blood pressure crosses accepted thresholds. 8- Clinical practice guidelines recommend blood pressure monitoring weekly during the first cycle of therapy, and then at least every 2 to 3 weeks for the duration of anti-VEGF drug exposure
  • 18. • Interestingly, there is a growing belief that hypertension may act as a valuable biomarker of efficacy with anti-VEGF agents. • This was found with bevacizumab, axitinib and sorafenib and needs to proved in more prospective trials.
  • 19. • Management of hypertension
  • 20. A- non-pharmacologic interventions • avoid excessive alcohol consumption and excessive salt intake , • Avoidance of other aggravating drugs such as non-steroidal anti-inflammatory drugs, steroids, erythropoietin agonists and sympathomimetics is also recommended when clinically feasible
  • 21. B- Pharmacologic management There is no consensus on recommendations of specific antihypertensive regimens used to manage HTN related to angiogenesis antagonists. Treatment recommendations should be made on the basis of the potential risks and benefits associated with each unique drug and patient.
  • 22. USE of ACE (angiotensin-converting enzyme) inhibitors may be beneficial as they affect nitric oxide. The American Diabetes Association recommends use of angiotensin-receptor blockers as the treatment of choice in hypertensive patients with diabetes, frank proteinuria, and/or microalbuminuria. Sunitinib: Diuretics remain the first-line choice for treatment of HTN in all patient populations, except those with chronic kidney disease (CRD). Application of the general guidelines
  • 23.
  • 24. C- Modification of the anti-VEGF agent dose or schedule. • Depending on the type of anti-VEGF agent For patients receiving daily-dosed tyrosine kinase inhibitors of VEGF such as sunitinib or sorafenib, temporarily withholding or reducing the drug can be rapidly effective if hypertension is symptomatic or refractory to standard anti-hypertensive interventions. • Anti-VEGF agents with longer half-lives such as bevacizumab and aflibercept do not respond as quickly to withdrawal or dose reduction. So: • Do not start if ( systolic >160mmHg and diastolic >100mmHg), Aggressive anti-hypertensive efforts before ttt , close monitoring, if failed refer to hypertensive expert.
  • 25. Cardiovascular toxicity of molecularly targeted agents • Hypertension, • Ventricular Dysfunction • Qtc Prolongation • Thrombo-embolic complications
  • 26. Pathogenesis: • Myocardial cells have limited regenerative capacity, which renders the heart susceptible to transient as well as permanent drug effects • Drug-induced ventricular dysfunction can occur via several distinct mechanisms: Type I cardiotoxicity, as caused by anthracyclines, results in structural abnormalities of the cardiac ultrastructure and subsequent cell death and clinical heart failure. Type II cardiotoxicity ( induced by molecularly targeted agents (particularly trastuzumab) is caused by failure of myofibril contractile elements to exert coordinated activity, but cell death and clinical heart failure are not dominant features and is more likely to be reversible.
  • 27. PATHOGENESIS of Trastuzumab cardiotoxicity • Targeting ErbB2 (human epidermal growth factor type 2 / Her2) which has a role in normal myocyte function • Induces mitochondrial apoptosis. Mitochondria are essential for myocyte vitality, as they generate adenosine triphosphate (ATP), the “fuel” for muscle contractility and survival. It is possible that antibody dependent, cell-mediated cytotoxicity is a substantial contributor to impaired ErbB2 function in myocytes, although this hypothesis remains theoretical and has not been scientifically substantiated.
  • 28. Trastuzumab cardiotoxicity: Incidence : • In metastatic breast, trastuzumab administered in combination with anthracycline-based combination chemotherapy demonstrated a surprising 27% cardiotoxicity rate,versus 13% with chemotherapy alone. • Adjuvant breast cancer trastuzumab trials indicates that grade 3 or 4 cardiac toxicity occurred in 4.5% of patients receiving trastuzumab versus 1.8% in women who did not receive the drug. Risk factors: older age, concurrent administration chemotherapy or exposure to previous anthracyclines, baseline left ventricular dysfunction, coronary artery disease, uncontrolled hypertension, valvular heart disease, and cardiac arrhythmia. Non-cardiovascular risk factors may include chest wall radiation, diabetes and obesity . Ventricular recovery is variable, ranging from 1.5 months to 1.5 years, rechallenge after ventricular recovery is well documented
  • 29. Cardiotoxicity associated with other molecularly targeted agents • Lapatinib: low levels of cardiac toxicity of • 1.5−2.2%, almost always reversible, and almost always asymptomatic. • Sunitinib: mechanism uncertain, HF rate 2.7% to 11% with 41% recovered. left-ventricular ejection monitoring, be incorporated into standard practice for patients receiving sunitinib. • Imatinib: Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients treated with imatinib. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated • Bevacizumab and Alemtuzumab
  • 30. An oncologist’s approach to ventricular dysfunction 1. Baseline assessment of their LVEF. 2. Only patients with normal cardiac function and no symptoms of congestive heart failure as quantified by the New York Heart Association (NYHA) classification system should be treated with a potentially ventricular-toxic agent. 3. Regular monitoring with physical examination as well as radiological measurement of left ventricular ejection fraction should ensue. 4. Any symptoms or signs suggestive of heart failure, functional cardiac assessment should occur.
  • 31.
  • 32. MANAGEMENT Once significant cardiac dysfunction is demonstrated, molecularly targeted therapy should be interrupted and aggressive management of heart failure should be implemented. • No specific strategy, so general population guidelines should be followed. • Serial reassessment of cardiac status is needed once dysfunction is demonstrated, rechallenge was tolerable with trastuzumab but follow-up is immature.
  • 33. Cardiovascular toxicity of molecularly targeted agents • Hypertension, • Ventricular Dysfunction • Qtc Prolongation • Thrombo-embolic complications
  • 34. Background and mechanisms of QT prolongation • On the ECG, the QT interval is measured from the beginning of the QRS complex to the end of the T wave in the lead without prominent U waves.
  • 35. • The QT interval on the ECG is a measure of ventricular depolarisation and repolarisation, corresponding to the duration of the ventricular action potential. • The interval is known to have biologic variation, most importantly with gender and heart rate. Formulae exist to account for these biologic confounders, and “corrected” QT (QTc) measurements of 450ms for men and 470ms for women are generally accepted as the upper limit of normal. • Ventricular arrhythmias, particularly torsade de pointes (TdP), correlate with a QTc interval of more than 500ms
  • 36. Causes of prolonged QT interval
  • 37.
  • 38. Nilotinib arsenic trioxide Prolongation of the QTc Interval
  • 39. The FDA has provided specific safety guidelines for QTc interval monitoring with arsenic trioxide administration (applicable when using other drugs): All patients must demonstrate a baseline QTc (best determined as a mean of three electrocardiograms more than 5 minutes apart) less than 500 ms, as well as maintain serum potassium greater than 4 mEq/L and magnesium greater than 1.8 mg/dL. If the QTc interval is greater than 500 ms or symptoms of syncope or palpitation occur, electrolyte replenishment and immediate hospitalization are advised, with cessation of arsenic trioxide treatment until QTc less than 460 ms.
  • 40. Cardiovascular toxicity of molecularly targeted agents • Hypertension, • Ventricular Dysfunction • Qtc Prolongation • Thrombo-embolic complications
  • 41. • Bevacizumab : A. Arterial thromboembolic events (ATEs): • Included cerebral infarction, transient ischemic attacks (TIAs), myocardial infarction (MI), and angina. • More frequently (4.4 versus 1.9%) and were more often fatal (0.7 versus 0.4%) in patients receiving bevacizumab in combination with chemotherapy compared with those receiving chemotherapy alone. • There is an increased risk of any ATE in bevacizumab- treated patients who have a prior history of stroke/heart attack (~5 fold), in those aged 65 years (~3 fold) and in patients with hypertension (~2 fold). Bevacizumab should be permanently discontinued in patients who develop ATEs.
  • 42. • Bevacizumab : B . Venous thromboembolic events (VTEs): • Include deep venous thrombosis, pulmonary embolism and thrombophlebitis. • VTEs occurred more often in patients receiving bevacizumab with chemotherapy than in those receiving chemotherapy alone. • If any grade 3-4 VTE occurs in a clinical trial, dosing with bevacizumab should be stopped for 3 weeks. Administration should only be continued when anticoagulation parameters have stabilised. Patients with symptomatic pulmonary embolism must not be treated with bevacizumab
  • 43. • IMMUNOMODULATORY AGENTS  Thalidomide and Lenalidomide use is associated with significantly increased incidence of deep venous thrombosis. Prophylactic anticoagulation is recommended during therapy of either drug.
  • 44. Skin toxicities of targeted therapies L/O/G/O www.themegallery.com
  • 45. • Skin Toxicity Of Epidermal growth factor receptor (EGFR) inhibitors. • Skin Toxicity Of Multikinase inhibitors (sorafenib, sunitinib,imatinib)
  • 46. • Skin Toxicity Of Epidermal growth factor receptor (EGFR) inhibitors. • Skin Toxicity Of Multikinase inhibitors (sorafenib, sunitinib,imatinib)
  • 47. Epidermal growth factor receptor (EGFR) inhibitors • EGFR targeted drugs consist of monoclonal antibodies to EGFR (e.g. cetuximab, panitumumab), • small-molecule tyrosine kinase inhibitors specific for EGFR (e.g. erlotinib, gefitinib), • dual kinase inhibitors inhibiting EGFR and HER2 (lapatinib), • pan-erbB inhibitors inhibiting EGFR and other erbB receptors (canertinib) • and other less specific inhibitors such as vandetanib inhibiting EGFR, vascular endothelial growth factor receptor (VEGFR) and RET.
  • 48. Clinical picture • Probably owing to the abundant expression of EGFR in the epidermis and its appendages (hair follic. • EGFR-inhibitor-induced skin toxicity consists of : an acneiform eruption, skin dryness leading to eczema and fissures, nail changes, hair changes, telangiectasia, hyperpigmentation and mucosal changesles, sebaceous glands)
  • 50. • The most frequently reported side effect of EGFR inhibitors is a dose-dependent acneiform eruption, occurring in 50% to 100% of patients. • The eruption is more or less confined to the seborrheic areas (rich in sebaceous glands): the face (especially the nose, the cheeks, the forehead and the chin), the scalp, the neck and retroauricular area,the shoulders and the upper trunk (typically V- shaped). The eruption tends to be more severe and widespread with monoclonal antibodies than with oral tyrosine kinase inhibitors (for which gastro- intestinal toxicity is a dose-limiting factor)
  • 51. • The skin lesions consist of sometimes itchy, erythematous follicular papules that may evolve into pustules. • The papulopustular eruption can appear just a few days (2−3 days for biologics, 7−10 days for small molecules) after treatment with the EGFR inhibitor, often reaching a maximum 2 to 3 weeks following initiation of therapy. • Slow spontaneous improvement of the rash is the rule when the EGFR inhibitor is continued even in the absence of dermatologic supportive treatment .
  • 52. • Flare up of the rash can occur following each infusion (in the case of intravenously administered monoclonal antibodies) and Sun exposure . • Acneiform eruption by EGFR inhibitors is essentially sterile but superinfection with Staphylococcus aureus may occur. • Skin areas that previously underwent radiotherapy are characteristically spared from the acneiform eruption. Concomitant cetuximab and radiotherapy on the other hand appear to increase the incidence of severe radiodermitis.
  • 53. EGFR-inhibitor-induced rash is acneiform should clearly be distinguished from acne vulgaris: indeed, comedones (blackheads and whiteheads) − the hallmark of true acne are lacking and so are nodules. Moreover, itchiness is not infrequent in EGFR inhibitor- induced acneiform but is absent in acne vulgaris. Finally, scalp involvement is rare in acne but frequent in patients receiving EGFR inhibitors.
  • 55. • EGFR inhibitors often gradually develop a dry skin over weeks. • Old patient age, previous therapy with cytotoxics and a history of atopic eczema will accentuate the cutaneous dryness, which manifests with dry, scaly, itchy skin. • The xerosis may develop into chronic asteatotic eczema • secondary infection • Painful fissures
  • 56. Nail changes • In 10−15% of patients, do not start earlier than 4−8 weeks after the initiation of the EGFR inhibitor • Paronychia very painful inflammation of the nail fold. (caused by epidermal cell growth arrest and differentiation • Induced by the EGFR inhibitor)
  • 57. Hair changes • Very characteristic are the long, curly, rigid eyelashes, termed Trichomegaly • The eyebrows become thicker and more rigid as well, with lateral thinning. • Slow growth of scalp hair,and beard.
  • 58. Other skin toxicities • Telangiectasia • The telangiectasia together with facial erythema, tenderness and follicular papulopustules in the absence of comedones creates a rosacea-like picture of the face. Unlike other telangiectasia, the lesions tend to fade over months usually leaving some hyperpigmentation • Hyperpigmentation • Mucosal changes: Conjunctivitis,. Dry mouth, apthous stomatitis. dry vulvovaginitis (especially in postmenopauzal (women) or balanitis.
  • 60. General measures and treatment principles • Adequate sun protective measures • avoid skin care products that dry out the skin • An emollient/hand cream can be used on the limbs and hands to prevent xerosis and fissures • Prophylactic treatment of acneiform eruption, as it occurs in 80% of patients on EGFR inhibitors: Minocycline 100 mg qd , oral tetracycline 500 mg bid and a regimen consisting of doxycycline 100 mg bid, topical hydrocortisone 1%, emollients and a sunscreen decreased severity of acneiform eruption.
  • 61. Treatment of acneiform eruption • Topical metronidazole and oral minocycline are the standard of treatment. • As a topical therapy, metronidazole is preferred (as a 2% preparation in cetomacrogol cream or as 0.75% Rozex® cream) because of its mildness, as it is normally used for the very sensitive skin of rosacea patients, twice a day or in between as needed on the first appearance of papulopustular lesions
  • 62. • Topical retinoids (adapalene, tazarotene) are used by some but lack rationale. • Acneiform eruption-associated itchiness can easily be controlled with an oral antihistaminic. • Calcineurin antagonists (tacrolimus or pimecrolimus), being used as first-line therapy in some American centres(irritant ,expensive) • Topical menadione (vitamin K3, an EGFR phosphatase inhibitor with promising • preclinical properties), not yet available for clinical use
  • 63. Despite its efficacy for EGFR inhibitor-dependent rash, oral isotretinoin should not be used as it may possibly interfere with EGFR-inhibitor antitumor activity by down regulating EGFR expression. Moreover, isotretinoin shares a large number of side effects with EGFR inhibitors (xerosis, sensitivity for S. aureus superinfection, paronychia, pyogenic granuloma), which may lower tolerability. • Systemic steroids are also to be avoided in the treatment of acneiform eruption as they may induce a similar eruption themselves; in addition, they may hamper the antibody-dependent cell-mediated cytotoxicity that is ascribed to EGFR-antibodies
  • 64. Treatment of xerosis, eczema and fissures • Hydrating measures oil in water creams (e.g. metronidazole cream) On the limbs, greasy (water in oil) creams or even ointments can be used for moderate to severe xerosis. • Eczema :a topical weak to medium strength corticosteroid cream is recommended for a short term (1 to 2 weeks). • Salicylic acid : fingertip eczema. • Infection :Treatment with topical (e.g. fusidic acid) or, in severe cases, systemic anti-S. aureus antibiotics can be added for 5−10 days. • Fissures: propyleneglycol 50% aqueous solution under plastic occlusion/salicylic acid 10% ointment, a hydrocolloid dressing or liquid cyanoacrylate glue
  • 65. Treatment of paronychia Antiseptic (e.g. chloramine, polyvidon iodine) oaks or creams are advised on a daily basis. When superinfection is suspected, swabs can be taken and oral anti-S. aureus antibiotics (e.g. flucloxacillin) given anti-yeast (e.g. nystatin) and a potent topical corticosteroid. Oral nonsteroidal anti-inflammatory drugs can be administered to control the pain. Silver nitrate application on a weekly basis improves pyogenic granuloma
  • 66. Treatment of hair changes, hyperpigmentation and telangiectasia • Eyelashes : laser epilation. • Telangiectasia : electrocoagulation or pulsed dye laser therapy. • Treatment of mucosal changes: • Eye : attificial tears, topical steroids,antibiotic • Tetracycline or antiseptic mouthwash alleviates • stomatitis symptoms. For aphtous ulcers of the mouth,topical steroids or anaesthetics can be used. • Dryness of the nose or the vagina responds fairly well to lubricants or ointments containing an antibiotic or antiseptic.
  • 67. Associations with outcome of therapy, predictive role Most of the published data have shown that patients in whom skin toxicity develops show a higher response rate than those without rash and significant correlations between occurrence of rash and increased survival have been found, with a trend towards improved overall survival and longer progression-free survival with increasing severity of rash. • Some research groups state that the rash is a surrogate indicator of an adequate degree of receptor saturation by EGFRI.
  • 68. • Skin Toxicity Of Epidermal growth factor receptor (EGFR) inhibitors. • Skin Toxicity Of Multikinase inhibitors (sorafenib, sunitinib,imatinib)
  • 69. Clinical picture Sorafenib (34%) and sunitinib (19%) may cause 1-hand-foot skin reactions (HFSR) • Dose-dependent. • Very characteristically localised to skin areas of friction or pressure. • It emerges in the first 2−3 weeks of treatment as sharply demarcated, erythematous, painful, oedematous and blistering lesions that evolve into extremely tender, inflamed calluses
  • 70.
  • 71. 2- Asymptomatic subungual splinter haemorrhages are seen in not less than 40−70% of patients on sorafenib or sunitinib. Sensitivity of subungual capillaries to microtrauma due to inhibition of VEGFR (with impaired angiogenesis) may be involved in its pathogenesis. 3- Dryness of the skin and/or mucous membranes (occasionally with stomatitis) are present in approximately 25% of patients receiving sorafenib/sunitinib. 4 . In the first weeks of treatment, sorafenib (and more rarely sunitinib) may cause a sometimes flaky erythema of the scalp and the face sparing the periorbital area, temporary alopecia, a transient dysaesthesia of the scalp skin with a burning and painful sensation, transient maculopapular rash. 5- Sunitinib: a yellow skin discolouring, caused by accumulation of this yellow molecule in the integument, reversible hair depigmentation, facialoedema.
  • 72. • Various skin reactions have been described with Imatinib: • A dose-dependent, periorbital, facial or even generalised oedema, appearing 2 weeks after starting the drug with very gradual regression later on. • Maculopapular eruptions (and, rarely, even more severe drug reactions such as vasculitis, acute generalised exanthematous pustulosis or toxic epidermal necrolysis necessitating permanent drug withdrawal). • Skin depigmentation but seldom also a paradoxical hyperpigmentation (especially of the nails) or repigmentation of grey hair. • Xerosis cutis and pruritus.
  • 73. Treatment and clinical management • To minimise the impact of hand-foot skin reaction: avoid drying of the skin; avoid friction and wear comfortable fitting clothes and shoes; treat pre-existing calluses or hyperkeratoses or mild hand- foot skin reaction with urea- or salicylic acid ointment. • Moderate HFSR: ultrapotent topical steroids and topical lidocaine to control the pain. Oral analgetics can be added accordingly. • For severe reactions, a (temporary) dose adjustment or interruption of the multikinase inhibitor is proposed when supportive dermalogic treatment offers insufficient relief. • Xerosis cutis: emollients and sometimes oral antihistamines. • The seborrheic dermatitis-like facial lesions respond well to topical • ketoconazole or weak steroids. • For the maculopapular eruption with sorafenib or imatinib, topical or systemic steroids and sometimes interruption of the drug are advised
  • 74. Renal toxicities of molecular targeted therapies: L/O/G/O www.themegallery.com
  • 75. Classification A. Nephron structure damage Glomerular lesions Glomerulonephritis and proteinuria Tubular lesions Fanconi syndrome or renal tubular acidosis Distal tubular alteration Interstitial lesions Allergic interstitial nephritis B. Vascular lesions Renal thrombotic microangiopathy
  • 76. Glomerulonephritis and proteinuria • Most of the toxicity is related to anti-VEGF • In the kidney, VEGF maintains the glomerular and peritubular capillary network. Use of an anti- VEGF agent may therefore disturb this network of blood vessels, leading to glomerular dysfunction and proteinuria.(altered glomerular permeability). • VEGF can act as a survival factor for podocytes and thereby prevent glomerulonephritis
  • 77. Glomerulonephritis • Different types of glomerulonephritis have been described during the use of molecular targeted therapies including: • membranoproliferative glomerulonephritis , • minimal change disease, • cryoglobulinemic glomerulonephritis and focal segmental glomerulosclerosis.
  • 79. Proteinuria: Bevacizumab 21- 41% low dose G3 22- 63% high dose VEGF TKIs Proteinuria and HTN Oedema as a direct consequence of proteinuria (it is one of the dose-limiting toxicities of sunitinib) MTOR inhibitors •increase in glomerular capillary pressure or directly by increasing Temsirolimus, sirolimus glomerular permeability/ injury. •Podocyte injury and focal segmental glomerulosclerosis
  • 80. Proteinuria should be monitored in patients receiving anti-VEGF therapy using the urine protein to creatinine ratio. • This index of proteinuria is commonly used in the nephrology literature and correlates well with 24-h protein excretion. • Dipstick values 2 or higher should be confirmed by the ratio of urine protein to creatinine or 24-h collection. • Bevacizumab therapy It is known that under this medication treatment should be interrupted in patients with proteinuria greater than 2 g/24 h
  • 81. Tubular lesions 1. Fanconi syndrome or renal tubular acidosis • imatinib : failure to reabsorp bicarbonate , and to secrete acid . Dysfunction of the proximal tubular cells and with phosphaturia, glycosuria, aminoaciduria, uricosuria and tubular proteinuria The principal feature of Fanconi’s syndrome is bone demineralisation due to phosphate wasting. This syndrome has been reported with different TKIs like imatinib
  • 82. 2. Distal tubular alteration This alteration is characterised by hypomagnesaemia. This phenomenon is one of the most frequent toxicities described with antibodies against EGFR. • Low Mg2+ inhibits endothelial migration and proliferation, late events absolutely required for the formation of new vessels, by desensitising endothelial cells to the effects of angiogenic factors. • The interaction between anti-EGFR agents and Mg2+ homeostasis could be partially responsible for the anticancer activity of these agents. • During anti-EGFR antibodies therapy, in addition to baseline assesment, serum Mg2+ level should be measured when fatigue or hypocalcaemia is encountered, and repleted as necessary
  • 83. Interstitial lesions • Common types of tubulointerstitial injury that can occur secondary to therapeutic agents include allergic interstitial nephritis, acute tubular necrosis, crystal nephropathy, tubular atrophy, and interstitial fibrosis • Allergic interstitial nephritis: Bevacizumab,sunitinib , progressive kidney dysfunction with proteinuria, together with peripheral eosinophilia and eosinophiluria, fever and rash Ttt : corticosteroids
  • 84. Vascular lesions • Renal thrombotic microangiopathy sirolimus, bevacizumab, sunitinib • Usually, withdrawal of the causing drug results in complete recovery or at least significant improvement of hypertension and renal involvement. • But, as limited therapeutic options, the alternative of maintaining treatment while blocking the renin–angiotensin system could be a good strategy for hypertension and proteinuria control
  • 85. • Combinations and interactions with other neprohotoxic drugs • Most of the experience of targeted therapies in combination with chemotherapy has been gained with bevacizumab and cetuximab no increase in toxicity was found .
  • 86.
  • 87. Gastrointestinal toxicities of novel agents in cancer therapy L/O/G/O www.themegallery.com
  • 88. Include: • Diarrhoea • Gastrointestinal bleeding, gastrointestinal perforation and wound- healing problems. • Hepatic toxicity. • Elevation of pancreatic enzymes
  • 89.
  • 90. Incidence, clinical pattern and pathophysiology of diarrhoea 1. Anti-epidermal growth factor receptor (EGFR) therapies • Appears withen 2 weeks after treatment initiation . • Correlated with the dose not plasma conc. • Mechanism : 1. EGFR are widely expressed in the normal colic mucosa in which they regulate both chloride secretion and sodium absorption by colonocytes . Therefore, EGFR inhibition can subsequently lead to secretory diarrhoea. 2. is also described to be involved in the maintenance of mucosal integrity. the stimulation of mucin production and the enhancement of prostaglandin synthesis. 4. Inhibition of EGFR might therefore lead to digestive lesions.
  • 91. Diarrhoea occurs in about 20−28% of patients undergoing anti-EGFR monoclonal antibody therapy but is rarely severe: 1−2% of grade 3−4. The incidence and severity of diarrhoea is higher with EGFR-TKIs than with anti-EGFR monoclonal antibodies, which have an incidence of 50−60% including 5% grade 3−4; diarrhoea is a dose limiting toxicity for TKIs. • Diarrhoea related to drug toxicity was also correlated in some studies with a clinical benefit and/or was a predictive factor of tumour response to TKI
  • 92. 2. Anti-HER2 (ErbB2) therapies • Trastuzumab is rarely associated with diarrhoea, with a total incidence of 7% without any grade 3−4 toxicity. • Lapatinib : diarrhoea occurred in 55% of lapatinib- treated patients versus 24% of controls, grade 3 occurred in 9%. • 40% of patients had the first episode of diarrhoea within 6 days after drug introduction for a median duration was of 7−9 days. • Diarrhoea was dose related and not associated with serum concentration.
  • 93. 3. Multi-targeted kinase inhibitors • Imatinib: 40% of patients, less than 5%, grade 3−4 diarrhoea. • The mechanism remains unknown, but one hypothesis is the inhibition of the colonic pace- maker cell (Cajal cells) which are c-Kit positive. • Sunitinib :D 20% of treated patients including 3% with grade 3 but no grade 4 diarrhoea. • Sorafenib: 39% of patients, 8% grade 3 and no grade 4. Diarrhoea was the most frequent adverse event that led to dose reduction (8% of cases)
  • 94. • Nilotinib: D in less than 10% of patients with only 1% grade 3−4. • Dasatinib : all grades of diarrhoea • in about 50% of patients, including 6% of grade 3−4. 4. Anti-angiogenic therapies: • Bevacizumab: diarrhoea occurred in only 12% of patients with no grade 3 or 4 diarrhoea. 5.Others • Temsirolimus: 27% of patients with less than 1% grade 3−4. • Bortezomib: all grades 30−40% grade 3 4−8% , no grade 4 diarrhoea. watery, with no bleeding, and associated with mild to moderate abdominal pain and cramps. Symptoms occur within the first 12−18 h after infusion initiation, and lasts for 1−2 days
  • 95.
  • 96. Management of diarrhoea in patients undergoing targeted therapy 1. It is important to exclude another cause of diarrhoea to avoid inappropriate treatment discontinuation. Exclude concomitant intake of laxative treatment, a past history of gastrointestinal tract surgery or look forClostridium or another infection. • 2. In most patients, diarrhoea resolves with conventional approaches, without dose modification It can be useful to rapidly start loperamide treatment with the classic administration of two 2 mg tablets after the first occurrence of diarrhoea followed by one tablet after consecutive episodes every 4 h. 3. In a minority of patients (<5% of cases), but particularly with orally administered small molecules, dose modification or treatment discontinuation is necessary .
  • 97. 4. If diarrhoea does not respond to limited intervariations, a dose of 0.5 mg subcutaneously (s.c.) of octreotide acetate every 8 h for 48−96 h may be recommended when diarrhoea is resistant to loperamide. Octreotide should be discontinued within 24 hours after the resolution of diarrhoea. 5- Severe diarrhea : hospitalisation for evaluation, intravenous fluid administration and electrolyte correction and/or antibiotics
  • 98. • Wound-healing complications, Gastrointestinal bleeding and gastrointestinal perforation
  • 99. • Wound-healing complications • Angiogenesis is one critical mechanism in the complex process of wound healing and bevacizumab, as an anti-angiogenic agent, has the potential to disrupt wound healing. • Bevacizumab is also associated with wound-healing complications in about 2−4.5% of patients who had surgery after treatment initiation. • Since the half-life of bevacizumab is approximately 21 days, it is recommended that therapy should not be initiated for at least 28 days following major surgery or until the wound is fully healed. • Furthermore, bevacizumab should be withheld 28−42 days before elective surgery.
  • 100. Gastrointestinal perforations • GI perforation (i.e., GI perforation, fistula formation, and/or intra-abdominal abscess), occurred in 2.4% of patients receiving bevacizumab alone or in combination with chemotherapy in 3 clinical trials for metastatic colorectal cancer. • life-threatening condition,fatal in 30% of cases. • Manifestations of these adverse GI effects included abdominal pain with constipation and vomiting (emesis). • The mechanism unknown. may be due to the shrinkage of tumour masses embedded in the intestinal wall, or may occur at the site of previous surgery. Other risk, factors include abscesses, diverticula or an inflammatory process involving the GI tract
  • 101. Gastrointestinal bleeding • Bevacizumab: Severe or fatal hemorrhages, including hemoptysis, GI bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding, occurred up to fivefold more frequently in patients receiving bevacizumab and chemotherapy than in those receiving chemotherapy alone. • sorafenib : was not associated with digestive haemorrhage or variceal bleeding in cirrhotic patients treated for hepatocellular carcinoma. • Imatinib, at a high dose of 800 mg/d was responsible for digestive haemorrhage-related death in four patients
  • 102. Targeted therapy and hepatic toxicity • Kit and PDGFR inhibitors  Imatinib  Sunitinib • Anti- EGRF :  Gefitinib  Erlotinib  Anti HER2:  Lapatinib (rare reversible)  Anti VEGF :  Bevacizumab (sclerosing cholangitis)
  • 103. Imatinib hepatic toxicity • In clinical trials, severe hepatotoxicity occurs in less than 5% of patients. • To date, a total of 24 case reports of severe hepatitisinduced by imatinib have been published. • Little is known about the mechanisms of liver toxicity but imatinib is metabolised by cytochrome P450. Therefore, an increase in toxic metabolites is possible in cases where there is use of enzymatic Inducers. • Also An idiosyncratic mechanism and an immuno- allergic mechanism were probable.
  • 104. Liver tests and prothrombin time should be performed before initiation of imatinib and then weekly or twice a month in the first month and then monthly thereafter or in case of symptoms. • Treatment has to be withdrawn in cases of grade-3 hepatotoxicity. Some authors have re- introduced imatinib at slowly increasing doses together with prednisone without recurrence of liver injury,, others suggest to modify the schema of treatment administration
  • 105. In conclusion, little is known about the mechanisms of hepatotoxicity due to targeted agents and management is often empirical. One should be cautious with the use of enzymatic inducers or inhibitors together with agents metabolised by the cytochrome pathway (e.g. imatinib, gefitinib, erlotinib). Hepatic function tests should be performed regularly . In case of liver dysfunction, other aetiologies should be ruled out and the use of the adverse drug reaction probability scale will help to evaluate the relationship between drug and hepatotoxicity.
  • 106. Elevation of pancreatic enzymes Elevation of lipase can be observed with the small oral multi-targeted therapies sorafenib, sunitinib and nilotinib.
  • 107. Recommendations of tests according to treatment
  • 108. Side effects and organ toxicity of protein kinase inhibitors observed in clinical studies.
  • 109.
  • 110.
  • 111.
  • 112. Take home message • Although novel, molecular targeted therapies are starting to fulfil their promise, changing how patients with cancer are treated and altering the natural history of many types of cancer, they are far from being a “magic bullet.”